Cancer is the second leading cause of death in North American, killing 557,000 people in 2002. The overall cancer risk is ½, representing tremendous burden to the all the individuals and fimilaies affected. Despite decades of intense research, a cure for most cancers is still not available. Recently, mechanism-based molecular therapy has emerged as increasingly attractive approach for cancer therapy.
Cancer development is underscored by two types of genetic alterations. One is the loss of function of tumor suppressor genes. The normal function of these genes is to keep cells in non-tumorigenic quiescent state. Another genetic alteration is the activation of oncogenes. While a variety of approaches are being developed to target oncogenes, targeting tumor suppressor genes is more challenging due to their loss of function in tumor development. However, recent studies show that even in malignant cells, tumor suppressor networks frequently remain intact but latent. Harnessing the powerful intrinsic tumor suppressors for cancer therapy has emerged an attractive new approach in contemporary drug discovery.
Since the discovery of the first member from an erythropoietin producing hepatoma cell line nearly two decades ago, the number of Eph receptor protein tyrosine kinases (RPTK) has increased to 16 in vertebrate, making them the largest subfamily of RPTKs. They are divided into EphA and EphB kinases according to sequence homology and ligand binding specificity of the membrane-anchored ligands called ephrins. While EphA kinases bind to GPI-anchored ephrin-As, EphB kinases target transmembrane ephrin-Bs. Earlier studies have established a regulatory role of Eph/ephrin interactions in neural patterning in developing nervous systems, primarily through repulsive guidance of growth cones and neurons. Genetic studies using knockout mice revealed a pivotal role of Eph kinases in the development of cardiovascular system. The past several years have seen explosive growth in investigation on Eph receptors and their ligands, leading to the identification of diverse cellular functions regulated by Eph/ephrin interactions including neural plasticity, brain size determination, blood clotting, epithelial morphogenesis and viral infection.